Wednesday, 15 August 2012

Propionic acid and autism

Another post, another organic acid (!) but please don't click away just yet as I attempt once again not to blind you with science. The topic of the day today is propionic acid (PPA) otherwise known as propanoic acid and the very tentative suggestions of some link to autism. 

Search on-line for propionic acid and you're quite likely to get lots of industrial chemical information about it including a materials safety data sheet (MSDS) (here) implying that this stuff is toxic, combustible and corrosive. So why on earth am I talking about it with regards to autism?

Well, like many things in modern life, the chemical industry isn't the only source of 'chemicals' as per our wonderful chemical factory that is the human body and the surprising effects of some of the bacteria which inhabit us. Not for the first time, I might add, has bacteria and biochemistry come together on this blog (see here) and probably not the last time either.

PPA is an organic acid - a short chain fatty acid - which as well as being used as a food additive / preservative and used in the process of polymer production apparently, is also what might be considered a natural product as a result of its endogenous production. Short chain fatty acid you say? Y'mean like the ones discussed not so long ago in relation to autism by Wang and colleagues? Yes, the very same.

Continuing with autism in mind, I am taken back to this news report from 2007 where Dr Derrick MacFabe discussed this piece of research* (followed up by this study** too) suggesting that you are what you eat in terms of foodstuffs and bacteria combining to produce PPA and what effect it had on the rat brain following "intraventricular infusions" (to you and me injecting the stuff directly into rat brains). Dr MacFabe has very definitely taken the lead when it comes to looking at PPA and autism. 

Indeed I was interested to see the effects of PPA administration on rat brains including activated microglia and decreased glutathione alongside the more overt effects on rat behaviour. Understanding that rats (like mice and fish) are not humans, indications of issues with glutathione have been quite strongly shown to be related to cases of autism and indeed the brain has become a recent focus for this area of research. As for microglia, I would once again refer you to this post by Paul Patterson on the suggested dietary habits of microglia in autism with the promise of a post on this research area soon.

Other research groups have also entertained a possible role for PPA in autism. The paper by El-Ansary and colleagues*** replicated the results from the MacFabe group and indeed added a few new aspects also making mention of lactate dehydrogenase and elevations in IL-6 among other things; both factors having been reported in connection to autism (here and here respectively). I think we can, with some degree of confidence, assume from this collected work, that propionic acid injections are probably not good news for rats.

We move onwards then to another piece of research by El-Ansary and colleague**** (full-text) looking at the possibility that supplementation with omega-3 fatty acids might afford some protection against the effects of PPA administration to rats. They reported that omega-3 supplementation did indeed alter some of the parameters associated with PPA administration including some interesting data on caspase-3, an executioner molecule involved in apoptosis previously reported in cases of autism (see here for more information). It seems rats fed a diet rich in omega-3 fatty acids might have some protection against various effects of PPA administration. I assume this ties into this paper by Thomas and colleagues***** (including Dr MacFabe).

So to summarise. An overlap between direct PPA administration and some key biochemical changes noted in cases of autism. Fine. A potential protective effect via use of omega-3 fatty supplementation from PPA administration. OK (fatty acids have some history in cases of autism as per this older post). PPA found to be elevated in cases of autism (based on the analysis of stools). Right.

Reading all that might convince some people of a role for PPA in autism but I'm going to play devil's advocate for a second and suggest why we need more research in this area. First, as mentioned rats aren't human beings. Rats might make good models for human being - as do some mice - but rats are not human beings. Second, administration of PPA was either intracerebroventricularly or at "neurotoxic doses" over 3 days (250mg/kg body weight). Either of these two factors whilst good for studying rats in a lab over a relatively short space of time is probably not going to be representative of chronic PPA exposure in people with autism. Unless of course that is, that something causes a huge acute surge in PPA that is. Finally(!) aside from the Wang findings on fecal PPA levels, the research in this area is still a little bit scant in terms of PPA levels in other biofluids. I haven't for example, seen anything as of yet looking at whether rates of the metabolic disorder propionic acidaemia is any more prevalent in cases of autism than not autism or likewise whether propionic acidaemia is accompanied by an increase in cases of autism accepting the seriousness and poor prognosis of this rare metabolic conditions. A few possible routes to further study perhaps.

That being said, I am still intrigued about propionic acid and the research done so far with regards to autism whether animal model-based or direct measurement. The whole connection back to short chain fatty acids, digestion and gut bacteria is an interesting and very under-researched area with autism in mind -  indeed with lots of other behavioural / cognitive / psychiatric conditions in mind. Could it hurt to put a little more research efforts into this area?

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MacFabe DF. et al. Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behavioral Brain Research. 2007; 176: 149-169.

** MacFabe DF. et al. Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: Relevance to autism spectrum disorder. Behavioral Brain Research. 2011; 217: 47-54.

*** El-Ansary AK. et al. Etiology of autistic features: the persisting neurotoxic effects of propionic acid. Journal of Neuroinflammation. April 2012.
DOI: 10.1186/1742-2094-9-74

**** El-Ansary AK. et al. On the protective effect of omega-3 against propionic acid-induced neurotoxicity in rat pups. Lipids in Health & Disease. 2011; 10: 142.

***** Thomas RH. et al. The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders. Journal of Neuroinflammation. 2012; 9: 153.

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ResearchBlogging.org El-Ansary AK, Ben Bacha A, & Kotb M (2012). Etiology of autistic features: the persisting neurotoxic effects of propionic acid. Journal of neuroinflammation, 9 (1) PMID: 22531301